ANTI-ATHEROSCLEROTIC ARYL COMPOUNDS

Description

[0001] The present invention is concerned with a novel genus of diaryl compounds, with processes for their preparation, with medicaments containing them and with their use as therapeutic agents, particularly in the prophylaxis and treatment of atherosclerosis.

[0002] The enzyme acyl coenzyme A - cholesterol acyl transferase (ACAT) is known to be involved in the intestinal absorption of cholesterol and in the accumulation of cholesterol as cholesterol esters in the arterial wall. Thus compounds which inhibit ACAT have the potential of demonstrating both potent hypocholesterolaemic activity and a decrease in arterial cholesterol deposition.

[0003] A group of compounds known collectively as 'fibrates' which give rise to a modest decrease in LDL-cholesterol, a significant decrease in triglycerides and a marked elevation of HDL-cholesterol in the plasma have been found useful in the treatment of Type IIA, IIB, III, IV and V hyperlipidaemias. The increase in the level of HDL-cholesterol is particularly important since it facilitates the removal of free cholesterol from the arterial wall for return to the liver ('reverse cholesterol transport').

[0004] It follows that a drug combining the hypocholesterolaemic/anti-atherosclerotic properties of an ACAT inhibitor with hypolipidaemic/HDL-enhancing properties would be particularly useful in the prophylaxis and treatment of atherosclerosis, the enhanced HDL-cholesterol level induced giving rise to an increase in the capacity of the reverse cholesterol transport mechanism to remove the free cholesterol resulting from ACAT inhibition in the arterial wall. Such a drug would be especially beneficial to Type IIA and Type III patients having both high serum cholesterol and triglyceride levels who are at particular risk of contracting coronary heart disease.

[0005] US-A-4623662 relates to urea and thiourea compounds, and their use in the treatment of atherosclerosis.

[0006] On the basis of the foregoing, we have disovered a series of novel compounds having potential hypolipidaemic/hypocholesterolaemic activity.

[0007] According to the present invention, therefore, there is provided a compound of formula (I)

wherein

Ar is

a mono- or bicyclic aromatic group optionally containing one or two heteroatoms independently selected from nitrogen, oxygen and sulphur, said group being optionally substituted by one or more atoms or groups independently selected from halogen, nitro, amino, -NRR¹ where R and R¹ are independently selected from hydrogen, C_1-8 alkyl and C_1-8 alkanoyl, cyano, carboxyalkoxy, alkoxycarbonylalkoxy, C_1-8 alkyl (including cycloalkyl and cycloalkylalkyl), C_1-8 alkoxy (including cycloalkoxy and cycloalkylalkoxy), C_1-8 thioalkyl, said alkyl, alkoxy and/or thioalkyl group(s) being optionally substituted by one or more halogen atoms, aryl, aryloxy, aralkyl and aralkyloxy, said aryl, aryloxy, aralkyl and/or aralkyloxy group(s) being optionally substituted by one or more atoms or groups independently selected from halogen, alkyl, alkoxy, alkanoyl, hydroxyalkyl, perfluoroalkyl, perfluoroalkoxy, carboxyalkoxy, alkoxycarbonylalkoxy, and C_3-8 polyether groups containing from one to three oxygen atoms;

D is

-CH₂-, -NH- or -O-;

E is

-N〈 or -CH〈;

G is

hydrogen, C_1-12 straight, branched, or cyclic alkyl, or aralkyl, said aralkyl group being optionally substituted by one or more atoms or groups independently selected from halogen, amino, N-(C_1-6 alkyl)amino, N,N-di(C_1-6 alkyl)amino, C_1-6 alkyl and C_1-6 alkoxy, or a C_3-8 polyether group containing one to three oxygen atoms;

J is

a bond or C_1-6 straight or branched alkylene;

n is

an integer of from 0 to 10;

R and R¹

are as hereinbefore defined; and

K is

-CH₂OH, -CHO, -CONHCH₂CONH₂, -CONH(C_1-6 alkyl), -OC(C_1-4 alkyl)₂ OCOheceroaryl, -CO₂R² where R² is hydrogen, C_1-8 alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or a C_3-8 polyether group containing from one to three oxygen atoms, or -CONHAr' where Ar' is phenyl optionally substituted by one or more atoms or groups selected from fluorine, nitro, -NRR¹ where R and R¹ are as hereinbefore defined, C_1-6 alkyl and C_1-6 alkoxy, said alkyl and/or alkoxy group(s) being optionally substituted at the terminal carbon by -CO₂R³ where R³ is C_1-6 alkyl;

and salts and physiologically functional derivatives thereof.

[0008] Salts of compounds of formula (I) suitable for use in medicine are those which are physiologically acceptable. However, non-physiologically acceptable salts are within the scope of the present invention for use as intermediates in the preparation of the compounds of the invention and their physiologically acceptable salts and physiologically functional derivatives.

[0009] The "physiologically functional derivatives" referred to herein are compounds which are converted in vivo to a compound of formula (I) or one of its physiologically acceptable salts.

[0010] Preferred compounds of formula (I) having particularly good ACAT inhibiting/fibrate-like properties include those wherein

Ar is

phenyl or naphthyl substituted by one or more atoms or groups independently selected from halogen, C_1-8 alkyl C_1-8 alkoxy (including cycloalkylalkoxy), said alkyl and/or alkoxy group(s) being optionally substituted by one or more halogen atoms, C_1-8 thioalkyl, aryl, aryloxy and aralkyloxy, said aralkyloxy group being optionally substituted by alkyl, alkanoyl, or hydroxyalkyl;

D is

-NH- or -O-;

E is

-N〈;

G is

C_5-8 straight or branched alkyl, (4-halophenyl)C_1-3 alkyl, or [4-di(C_1-6 alkyl)aminophenyl]C_1-3 alkyl;

J is

C_1-3 alkylene;

n is

an integer of from 0 to 4;

R and R¹

are respectively hydrogen and C_1-4 alkyl or are both C_1-4 alkyl; and

K is

-CO₂R² where R² is hydrogen or C_1-4 alkyl, or -CH₂OH;

and physiologically acceptable salts and physiologically functional derivatives thereof.

[0011] Particularly preferred compounds of the invention are 2-(4-(2-[3-(2,4-dimethoxyphenyl)-l-heptylureido]ethyl)phenoxy)-2-methylpropionic acid, 2-(4-(2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl)phenoxy)-2-methylpropionic acid, 2-(4-[3-(2,4-dimethoxyphenyl)-1-heptylureidomethyl]phenoxy)-2-methyl-propionic acid, 2-(4-[1-heptyl-3-(2,4,6-trichlorophenyl)ureidomethyl]phenoxyl-2-methylpropionic acid, 2-(4-[1-(3,3-dimethylbutyl)-3-(2,4-dimethoxyphenyl)ureidomethyl]phenoxy}-2-methylpropionic acid, 3-(2,4-dimethoxyphenyl)-1-heptyl-1-[4-(2-hydroxy-1-methylethoxy)benzyl]urea, 3-(2,4-dimethylphenyl)-1-heptyl-1-[4-(5-hydroxy-4,4-dimethylpentyloxy)benzyl]urea and their physiologically acceptable salts and physiologically functional derivatives.

[0012] According to further aspects of the invention, there are also provided:

(a) compounds of formula (I) and physiologically acceptable salts and physiologically functional derivatives thereof for use as a therapeutic agent;

(b) pharmaceutical formulations comprising a compound of formula (I) and/or one of its physiologically acceptable salts or physiologically functional derivatives and at least one pharmaceutical carrier;

(c) the use of a compound of formula (I) or of a physiologically acceptable salt or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which an ACAT inhibitor and/or a fibrate is indicated; and

(d) processes for the preparation of compounds of formula (I) and salts and physiologically functional derivatives thereof.

[0013] With regard to aspects (a) and (c), the ability of compounds of formula (I) to inhibit ACAT activity renders them useful as hypocholesterolaemics and for reducing the steady state concentration of cholesterol and cholesterol ester in the arterial wall. Similarly, the fibrate-like activity of compounds of formula (I) renders them useful as hypolipidaemics and for increasing the capacity of the reverse cholesterol transport mechanism to remove free cholesterol from the arterial wall.

[0014] On the basis of their ability to regress established atherosclerotic plaque and retard the build-up of fresh lesions, compounds of formula (I) find application in both the prophylaxis and treatment of atherosclerosis.

[0015] In view of their hypocholesterolaemic/hypolipidaemic properties, compounds of formula (I) and their physiologically acceptable salts and physiologically functional derivatives may also find application in the prophylaxis and treatment of pancreatitis, in 'shifting' the oxygen affinity of human haemoglobin to improve myocardial function, for example, in the treatment of ischaemic tissue, and as uricosuric agents for reducing elevated plasma uric acid levels arising from, for example, hypertriglyceridaemia. The compounds of the invention also exhibit calcium antagonism in the ileum, stimulate hepatic fatty acid oxidation in the liver and have the potential to lower plasma triglycerides and elevate plasma HDL-cholesterol.

[0016] Hereinafter all references to "compound(s) of formula (I)" refer to compound(s) of formula (I) as defined above including their physiologically acceptable salts and physiologically functional derivatives.

[0017] The amount of a compound of formula (I) which is required to achieve the desired biological effect will, of course, depend on a number of factors, for example, the specific compound chosen, the use for which it is intended, the mode of administration and the clinical condition of the recipient. In general, the daily dose will be in the range 5mg to lg, for example, 10mg per day. An intravenous dose may, for example, be in the range 100mg to lg, which may conveniently be administered as an infusion of from lmg to 100mg per minute. Infusion fluids suitable for this purpose may contain, for example, from 0.1mg to 10mg, typically lmg, per millilitre. Unit doses may contain, for example, from 100mg to lg of the active compound. Thus ampoules for injection may contain, for example, from 100mg to 500mg and orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, from 100mg to lg, typically 200mg. In the case of physiologically acceptable salts, the weights indicated above refer to the weight of the ion derived from the compound of formula (I).

[0018] For the prophylaxis or treatment of the conditions referred to above, the compounds of formula (I) may be used as the compond per se, but are preferably presented with an acceptable carrier in the form of a pharmaceutical formulation. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be deleterious to the recipient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances may also be present including other compounds of formula (I). The formulations of the invention may be prepared by any of the wellknown techniques of pharmacy consisting essentially of admixing the components.

[0019] The formulations include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound of formula (I) which is being used.

[0020] Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of formula (I); as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and the carrier (which may constitute one or more accessory ingredients). In general, the formulations are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or moulding a powder or granules of the compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

[0021] Formulations suitable for buccal (sub-lingual) administration include lozenges comprising a compound of formula (I) in a flavoured base, usually sucrose and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

[0022] Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of formula (I), preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of the active compound.

[0023] Formulations suitable for rectal administration are preferably presented as unit-dose suppositories. These may be prepared by admixing a compound of formula (I) with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0024] Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanoline, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from 0.1 to 15% w/w of the composition, for example, from 0.5 to 2%.

[0025] Compounds of formula (I) may be prepared by conventional means well known to a skilled person. Thus compounds of formula (I) wherein D is -NH- and E is -N〈 may be prepared by reacting a compound of formula (II)

wherein n, G, J, R and R¹ are as hereinbefore defined and K' is as hereinbefore defined for K or is a suitably protected form thereof, with a compound of formula (III)

        Ar-NCO     (III)

wherein Ar is as hereinbefore defined, typically in an aprotic polar solvent, for example, dichloromethane, and, if necessary, deprotecting the product.

[0026] Compounds of formula (II) wherein J is -CH₂- may be prepared by reacting a compound of formula (IV)

wherein n, R, R¹ and K' are as hereinbefore defined, with a compound of formula (V)

        G-NH₂     (V)

wherein G is as hereinbefore defined, typically by refluxing in a polar solvent, for example, ethanol, and reducing the resulting imine by, for example, hydrogenation over Pd/C.

[0027] Compounds of formula (IV) may be prepared by reacting commercially available 4-hydroxybenzaldehyde with a compound of formula (VI)

wherein n, K', R and R¹ are as hereinbefore defined and L is a suitable leaving group, for example, bromo, typically by refluxing in a polar solvent, for example, ethanol, in the presence of potassium carbonate.

[0028] Compounds of formula (II) wherein J is C_2-6 straight or branched alkylene may be prepared by reacting a compound of formula (VII)

wherein n, J, K', R and R¹ are as hereinbefore defined, with a compound of formula (VIII)

        G'-CHO     (VIII)

wherein G' is as hereinbefore defined for G less a terminal methylene group, typically by mixing the two compounds together and reducing the resulting imine by, for example, hydrogenation over Pd/C.

[0029] Compounds of formula (VII) may be prepared by reacting a compound of formula (IX)

wherein J is as hereinbefore defined and P is a suitable protecting group, for example, benzyloxycarbonyl, with a compound of formula (VI) as hereinbefore defined, typically by refluxing in a polar solvent, for example, ethanol, in the presence of a base, for example, KOH, and deprotecting the product by, for example, in the case where P is benzyloxycarbonyl, hydrogenation over Pd/C.

[0030] Compounds of formula (IX) may be prepared from the corresponding amine (X) by treatment with a compound of formula (XI)

        L-P     (XI)

wherein L is a suitable leaving group, for example, chloro, and P is a suitable amino protecting group, for example, benzyloxycarbonyl.

[0031] Compounds of formula (III), (V), (VI), (VIII), (X) and (XI) are commercially available or may be prepared by methods well known to a skilled person or obtainable from the chemical literature.

[0032] Optional conversion of a compound of formula (I) to a corresponding salt may be effected by reaction with the appropriate acid or base. Optional conversion to a physiologically functional derivative may be carried out by methods well known to a skilled person or obtainable from the chemical literature.

[0033] For a better understanding of the invention, the following Examples are given by way of illustration.

Synthetic Example 1

Preparation of 2-(4-{[3-(2,4-dimethoxyphenyl)-1-heptylureido]methyl}-phenoxyl-2-methylpropionic acid

[0034] 

(a) Ethyl 2-(4-formylphenoxy)-2-methylpropanoate
4-Hydroxybenzaldehyde (24.4g, Aldrich) was dissolved in absolute ethanol (470ml) and anhy. K₂CO₃ (27.6g) and ethyl 2-bromoisobutyrate (39.0g, Aldrich) added. The resulting mixture was refluxed overnight, allowed to cool and the solvent removed in vacuo. The residue was suspended in water (300ml) and extracted with CH₂Cl₂. The combined organic layers were washed with 1.ON aqu. NaOH and water, then dried over MgSO₄. Removal of the solvent in vacuo and vacuum distillation of the residue gave the desired product (18.8g, bp 110-118°C/0.1mm Hg).

(b) Ethyl-N-n-heptyl-2-(4-aminomethylphenoxy)-2-methylpropanoate
The product from step (a) (4.72g) was dissolved in absolute ethanol (140ml) and n-heptylamine (2.3g, Aldrich) added. The resulting solution was refluxed for one hour, 10% Pd/C added and the suspension placed on a Paar hydrogenation apparatus - uptake of hydrogen ceased after approximately ten minutes. The suspension was filtered and the filtrate evaporated in vacuo to give the desired product as a clear oil (6.2g).

(c) N-(2,4-Dimethoxyphenyl)-N'-heptyl-N'-{p-[2-(carbethoxy)isoprooxy]phenyl}methylurea
The product from step (b) (3.49g) was dissolved in CH₂Cl₂ (100ml) and 2,4-dimethoxyphenylisocyanate (1.9g, Aldrich) added. The resulting solution was stirred for 8 hours and then evaporated in vacuo. The residue was flash chromatographed through a silica column using hexanes/CH₂Cl₂/EtOAC (38:31:31) as eluant to give the desired product as a colourless oil (4.9g).

(d) N-(2,4-Dimethoxyphenyl)-N'-heptyl-N'-{p-[2-(carboxy)isopropoxy]-phenyl}methylurea
The product from step (c) (4.85g) was dissolved in ethanol (25ml) and 1.0N aqu. NaOH (15ml) added. The resulting solution was heated to effect dissolution and then refluxed for 4 hours. After cooling, CH₂Cl₂ (100ml) and 1.0N aqu. HCl (60ml) were added. The organic layer was separated and the aqueous layer extracted with additional CH₂Cl₂. The combined organic layers were washed with water, dried over MgSO₄ and evaporated in vacuo to leave a pale yellow viscous oil which upon crystallization from hexanes/ether gave the desired product as a colourless solid (2.1g), mp 80-81°C.
¹H NMR (500MHz, δ, CDCl₃): 6.33-8.04 (m, 8H, aromatic, NH), 4.44 (s, 2H, CH₂-phenyl, 3.61/3.69 (2 x s, 6H, 2,4-(OCH₃)₂), 3.26 (t, 2H, N-CH₂-(CH₂)₅CH₃) and 0.65-1.80 (m, 19H, (CH₂)₅CH₃, (CH₃)₂C)
FAB MS: (H-1)⁺ = 485
Elemental analysis (C₂₇H₃₈N₂O₆): C 66.57% (66.64%), H 7.90% (7.87%), N 5.72% (5.76%)

Synthetic Example 2

Preparation of 2-(4-{2-[3-(2,4-dimethoxyphenyl)-1-heptylureido]ethyl}-phenoxy)-2-methylpropionic acid

[0035] 

(a) Carbobenzyloxytyramine
Sodium bicarbonate (12.6g) was dissolved in distilled water (250ml) and tyramine (20.6g) added. The resulting suspension was heated to boiling to dissolve the tyramine, then cooled to room temperature. Benzyl chloroformate (25.6g) was added while stirring and with occasional vigorous shaking. After stirring and shaking for an additional 1.5 hours, the precipitate was filtered off and washed with distilled water. The solid was dissolved in ether (250ml) and washed with distilled water. The organic layer was dried over MgSO₄ and evaporated in vacuo to give a residue which solidified upon cooling. Recrystallization from ether/hexane gave the desired product as colourless crystals, m.p. 96-98°C.

(b) Ethyl 2-[4-(2-carbobenzyloxyamino)ethyl]phenoxy-2-methylproionate
The product from step (a) (42.8g) and KOH (6.2g) were dissolved with warming in absolute ethanol (600ml). Ethyl 2-bromoisobutyrate (21.7g) was added and the resulting solution refluxed for 5.5 hours. Additional KOH (4.0g) and ethyl 2-bromoisobutyrate (11.3g) were then added and refluxing continued for 16.5 hours. After cooling, the precipitated KBr was removed by filtration and the filtrate evaporated in vacuo to give a light brown oil. The oil was dissolved in CH₂Cl₂ (500ml), washed with 1.0N aqu. NaOH, satd. aqu. NaCl, 1.0N aqu. HCl and satd. aqu. NaCl, dried over MgSO₄ and the solution evaporated in vacuo. The residue was flash chromatographed through a silica column using hexanes/CH₂Cl₂/EtOAc (50:25:25) as eluant to give the desired product as a colourless oil (23.5g).

(c) Ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate
The product from step (b) (2.7g) was dissolved in ethanol (100ml) and 10% Pd/C (0.3g) added. Paar hydrogenation for 45 minutes resulted in a drop in bottle pressure from 48.5 to 41.0 psi. The Pd/C was removed by filtration and the filtrate evaporated in vacuo to give the desired product as a colourless oil (1.5g).

(d) Ethyl 2-[4-(heptylaminoethyl)phenoxy]-2-methylpropionate
The product from step (c) (1.5g) and heptaldehyde (0.7g) were mixed together in a observably exothermic reaction and the product dissolved in absolute ethanol (100ml). Paar hydrogenation for 1.0 hour resulted in a drop in bottle pressure from 49.0 to 42.7 psi. The Pd/C was removed by filtration and the filtrate evaporated in vacuo to give the desired product as a colourless oil (2.1g).

(e) Ethyl 2-(4-{2-[3-(2,4-dimethoxyphenyl)-1-heptylureido]ethyl}-phenoxy)-2-methylpropionate
The product from step (d) (2.lg) and 2,4-dimethoxyphenylisocyanate (1.1g, Aldrich) were dissolved in CH₂Cl₂ (50ml). The resulting solution was stirred at room temperature for 17 hours and then evaporated in vacuo. The residue was flash chromatographed through a silica column using hexanes/CH₂Cl₂/EtOAc (50:25:25) as eluant to give the desired product as a very light brown oil (2.0g).

(f) 2-(4-{2-[3-(2,4-Dimethoxyphenyl)-1-heptylureido]ethyl}phenoxy)-2-methylpropionic acid
The product from step (e) (2.0g) was dissolved in absolute ethanol (50ml) and 1.0N aqu. NaOH (30ml) added. The resulting solution was refluxed for 0.5 hour, cooled to room temperature, acidified with 2.ON aqu. HCl (100ml) and extracted with CH₂Cl₂. The combined organic layes were washed with water and satd. aqu. NaCl, dried over MgSO₄ and evaporated in vacuo to give a viscous yellow oil. Repeated recrystallization from ether/hexanes gave the desired product as colourless crystals (1.5g), mp 95-96°C.
¹H NMR (500MHz, δ, CDCl₃) 6.44-7.99 (m, 7H, aromatic), 3.82 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 3.45 (t, 2H, CH₂), 3.18 (s, 3H, CH₂), 2.84 (s, 3H, CH₂), 1.55-1.58 (m, 8H, C(CH₃)₂, CH₂), 1.26-1.30 (m, 8H, (CH₂)₄) and 0.86 (t, 3H, (CH₂)₆CH₃)
FAB MS: (H-1)⁺ = 499
Elemental analysis (C₂₈H₄₀N₂O₆); C 67.28% (67.17%), H 8.10% (8.05%), N 5.57% (5.60%)

Synthetic Example 3

Preparation of 2-(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl} phenoxyl-2-methylpropionic acid

[0036] 

(a) Ethyl 2-[4-(heptylaminoethyl)phenoxyl-2-methylpropionate
As for steps (a) to (d) of Synthetic Example 2.

(b) Ethyl 2-(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}-phenoxyl-2-methylpropionate
The product from step (d) (3.3g) was dissolved in CH₂Cl₂ (100ml) and 2,4-difluorophenylisocyanate (1.6g, Aldrich) added. The resulting solution was stirred overnight at room temperature and then evaporated in vacuo. The residue was flash chromatographed through a silica column using toluene/hexanes/CH₂Cl₂/EtOAC (50:30:10:10) as eluant to give the desired product as a colourless oil (4.8g).

(c) 2-(4-{2-[3-(2,4-Difluorophenyl)-1-heptylureido]ethyl}phenoxyl-2-methylpropionic acid
The product from step (e) (2.4g) was dissolved in absolute ethanol (25ml) and 1.0N aqu. NaOH (10ml) added. The resulting solution was stirred at room temperature for 3.7 hours, acidified with 1.0H aqu. HCl (100ml) and extracted with CH₂Cl₂. The combined organic layers were washed with brine (50ml), dried over HgSO₄ and evaporated in vacuo to give a colourless oil which was flash chromatographed through a silica column using hexanes/CH₂Cl₂/EtOAc (50:25:25) as eluant to give the desired product as a very pale yellow viscous oil (1.4g).
¹H NMR (500MHz, δ, CDCl₃): 6.77-7.99 (m, 6H, aromatic), 6.27 (s, 1H, NH), 4.10 (q, 4H, OCH₂), 3.48 (t, 2H, CH₂), 3.19 (t, 2H, CH₂), 2.84 (t, 2H, CH₂), 1.59 (m, 2H, CH₂), 1.53 (s, 6H, (CH₃)₂C), 1.22-1.28 (m, 10H, (CH₂)₅) and 0.86 (t, 3H, (CH₂)₆CH₃)
FAB MS: (H-1)⁺ = 475
Elemental analysis (C₂₆H₃₄F₂N₂O₄): C 65.65% (65.53%), H 7.24% (7.19%), N 5.86% (5.88%).

Synthetic Examples 4-98

[0037] The following compounds of formula (I) were prepared by methods analogous to those of Synthetic Examples 1 to 3. All compounds have ¹H NMRs and elemental analyses consistent with the proposed structures.

4) Ethyl 2-{4-[3-(4-chlorophenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, mp 46-48°C;

5) 2-{4-[3-(4-Chlorophenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionic acid, mp 120-122°C;

6) Ethyl 2-[N'-(4-chloro-2-trifluoromethylphenyl)-N-heptylureidomethylphenoxy]-2-methylpropionate, colourless oil;

7) Ethyl 2-(4-{[1-heptyl-3-(2,4,6-trichlorophenyl)ureido]methyl}-phenoxy)-2-methylpropionate, pale yellow liquid;

8) 2-(4-{[1-Heptyl-3-(2,4,6-trichlorophenyl)ureido]methyl}phenoxy)-2-methylpropionic acid, mp 52-54°C;

9) Ethyl 2-[3-(2,4-difluoro-6-methoxyphenyl)-1-heptylureidomethylphenoxy]-2-methylpropionate, colourless oil;

10) 1-(2,4-Difluoro-6-methoxyphenyl)-3-[4-(2-hydroxy-1,1-dimethylethoxy)benzyl]urea, colourless oil;

11) 2-{4-(3-(2-Ethoxyphenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropanol, pale tan oil;

12) 2-(4-{[3-(2,4-Dimethoxyphenyl)-1-heptylureido]methyl}phenoxy)-propionic acid, mp 98-99°C;

13) Ethyl 5-(4-{[3-(2,4-dimethoxyphenyl)-1-heptylureido]methyl}phenoxy-2,2-dimethylvalerate, colourless oil;

14) 2-[4-({1-[2-(4-chlorophenyl)ethyl]-3-(2,4-dimethoxyphenyl)ureido}methyl)phenoxy]-2-methylpropionic acid, mp 118.5-120°C;

15) (4-{[3-(2,4-Dimethoxyphenyl)-1-octylureido]methyl}phenoxy)-2-methylpropionic acid, mp 62-64°C;

16) Ethyl (4-{[3-(2,4-dimethoxyphenyl)-1-pentylureido]methyl}phenoxy)-2-methylpropionate, yellow oil;

17) 2-(4-{[3-(2,4-Dimethoxyphenyl)-1-pentylureido]methyl}phenoxy)-2-methylpropionic acid, mp 119-120°C;

18) 2-(4-{[1-(3,3-Dimethylbutyl)-3-(2,4-dimethoxyphenyl)ureido]-methyl}phenoxy)-2-methylpropionic acid, mp 149-150°C;

19) 1-Heptyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)benzyl]-3-(2,4,6-trimethoxyphenyl)urea, mp 109-110°C;

20) 3-(2,4-Dimethoxyphenyl)-l-heptyl-1-[4-(2-hydroxy-1-methylethoxy)benzyl]urea, colourless oil;

21) Ethyl 2-[4-(N'-2-biphenylyl-N-heptylureidomethyl)phenoxy]-2-methylpropionate, mp 61-62°C;

22) 2-{4-[3-(2-Biphenylyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionic acid 0.75 potassium salt, no mp (amorphous solid);

23) Ethyl 2-{4-[1-heptyl-3-(2-phenoxyphenyl)ureidomethyl]phenoxy}-2-methylpropionate, pale tan gum;

24) 3-(2,4-Dimethylphenyl)-1-heptyl-1-{4-[(5-hydroxy-4,4-dimethylpentyl)oxy]benzyl}urea, colourless oil;

25) Ethyl 2-{4-[3-(2-ethoxy-4,6-difluorophenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, colourless oil;

26) Ethyl 2-{4-[3-(4-chloro-2-ethoxyphenyl)-1-heptylureidomethyl]-phenoxy}-2-methylpropionate, colourless oil;

27) Ethyl 2-(4-{[3-(2,4-dimethoxyphenyl)-l-heptylureido]methyl}-phenoxy)-2-methylpropionate, colourless oil;

28) Ethyl 2-(4-{[3-(5-chloro-2,4-dimethoxyphenyl)-1-heptylureido]-methyl}phenoxy)-2-methylpropionate, yellow oil;

29) Ethyl 2-{4-[3-(2-ethoxy-1-naphthyl)-l-heptylureidomethyl]phenoxy}-2-methylpropionate, mp 89-91°C;

30) Ethyl 2-[N'-(2,5-di-t-butylphenyl)-N-heptylureidomethylphenoxy]-2-methylpropionate, mp 82.5-84.5°C;

31) 2-{4-[3-(2-Biphenylyl)-1-heptylureidomethyl]phenoxy}-2-methylpropanol, colourless oil;

32) Ethyl 2-{4-[3-(4-fluorenyl)-l-heptylureidomethyl]phenoxy}-2-methylpropionate, mp 78-79°C;

33) Ethyl 2-{[3-(2-fluorophenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, colourless oil;

34) Ethyl 2-{4-[3-(2,6-difluorophenyl)-1-heptylureidomethyl]phenoxy}-isobutyrate, colourless oil;

35) Ethyl 2-{4-[3-(2,4-difluorophenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, colourless oil;

36) Ethyl 2-[4-(2,4-difluoro-N-heptylphenylacetamidomethyl)phenoxy]-2-methylpropionate, very pale yellow oil;

37) Ethyl 2-{4-[1-t-butyl-3-(2,4-difluorophenyl)ureidomethyl]phenoxy}-2-methylpropionate, mp 80-82°C;

38) Ethyl 5-{4-[3-(2,4-difluorophenyl)-1-heptylureidomethyl]phenoxy}-valerate, colourless oil;

39) Ethyl 2-(4-{3-[2-(4-t-butylbenzyloxy)-4,6-difluorophenyl]-1-heptylureidomethyl}phenoxy)-2-methylpripionate, colourless oil;

40) Ethyl 2-{N'-[2-(4-t-butylbenzyloxy)phenyl]-N-heptylureidomethyl]-phenoxy-2-methylpropionate, colourless oil;

41) Ethyl 2-(4-{N'-[2-(4-t-butylbenzyloxy)-4-chlorophenyl]-N-heptylureidomethyl}phenoxy)-2-methylpropionate, mp 76-78°C;

42) Ethyl 2-(4-{[(4-chlorophenoxy)carbonyl]heptylaminomethyl}phenoxy)-2-methylpropionate, no mp (amorphous solid);

43) Ethyl 2-{4-[3-(4-chlorophenyl)-1-dodecylureidomethyl]phenoxy}-2-methylpropionate, yellow oil;

44) Ethyl 2-(4-{[(4-chlorophenoxy)carbonyl]dodecylaminomethyl}phenoxy)-2-methylpropionate, colourless viscous oil;

45) Ethyl 5-{4-[3-(4-chlorophenyl)-1-heptylureidomethyl]phenoxy}valerate, colourless oil;

46) 1-(4-Chloro-2-trifluoromethylphenyl)-3-heptyl-3-[4-(2-hydroxy-2, 2-dimethylethoxy)benzyl]urea, colourless oil;

47) 2-{4-[3-(2,4-Dichlorophenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionic acid, mp 73-74.5°C;

48) Ethyl 2-{4-[3-(3,4-dichlorophenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, no mp (colourless wax);

49) Ethyl 2-{4-[1-dodecyl-3-(2,4,6-trichlorophenyl)ureidomethyl]phenoxy}-2-methylpropionate, colourless oil;

50) Ethyl 2-{4-[3-(4-chloro-2-nitrophenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, yellow oil;

51) Ethyl 2-{4-[1-heptyl-3-(2-methoxyphenyl)ureidomethyl]phenoxy}-2-methylpropionate, yellow oil;

52) Ethyl{4-[3-(4-methoxyphenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, no mp (colourless wax);

53) Ethyl 2-{4-[1-heptyl-3-(2-trifluoromethoxyphenyl)ureidomethyl]-phenoxy}-2-methylpropionate, colourless oil;

54) Ethyl 2-(4-{3-[2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl]-1-heptureidomethyl}phenoxy)-2-methylpropionate, pale tan oil;

55) 2-{4-[3-(4-Chloro-2-methoxyphenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionic acid, mp 121-122°C;

56) Ethyl 2-{4-[1-heptyl-3-(2-methylthiophenyl)ureidomethyl]phenoxy}-2-methylpropionate, colourless oil;

57) Ethyl 2-{4-[N'-(2-Ethoxyphenyl)-N-heptylureidomethyl]phenoxy}-2-methylpropionate, colourless oil;

58) Ethyl 2-{4-[3-(2,4-dichloro-6-ethoxyphenyl)-1-heptylureidomethyl]phenoxy)-2-methylpropionate, colourless oil;

59) 2-Ethoxyphenyl N-[4-(1-ethoxycarbonyl-1-methylethoxy)benzyl]-N-heptylcarbamate, colourless oil;

60) Ethyl 2-{4-[1-heptyl-3-(2-propoxyphenyl)ureidomethyl]phenoxy}-2-methylpropionate, colourless oil;

61) Ethyl 2-{4-[3-(2,6-dimethoxyphenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, colourless oil;

62) Ethyl 2-[4-(N-heptyl-2,4-dimethoxyphenylacetamidomethyl)phenoxy]-2-methylpropionate, pale tan oil;

63) 2-{4-[3-(2,4-Dimethoxyphenyl)-1-heptylureidomethyl]phenoxy}butyric acid, pale yellow oil;

64) 3-(2,4-Dimethoxyphenyl)-l-heptyl-1-[4-(1-hydroxymethylpropoxy)-benzyl]urea, tan oil;

65) 5-{4-[3-(2,6-Dimethoxyphenyl)-1-heptylureidomethyl]phenoxy}-2,2-dimethylvaleric acid, tan oil;

66) 2-{4-[1-Heptyl-3-(2,4,6-trimethoxyphenyl)ureidomethyl]phenoxy}-2-methylpropionic acid, mp 140-162°C;

67) Ethyl 2-(4-{1-[2-(4-chlorophenyl)ethyl]-3-(2,4-dimethoxyphenyl)-ureidomethyl}phenoxy)-2-methylpropionate, mp 89.5-91°C;

68) 2-{4-[3-(2,4-Dimethoxyphenyl)-1-nonylureidomethyl]phenoxy}-2-methylpropionic acid, mp 55-57°C;

69) Ethyl 2-{4-[3-(2,4-dimethoxyphenyl)-1-propylureidomethyl]phenoxy}-2-methylpropionate, mp 69-71°C;

70) 2-{4-[3-(2,6-Dimethoxyphenyl)-1-propylureidomethyl]phenoxy}-2-methylpropionic acid, mp 96-98°C;

71) Ethyl 2-{4-[1-t-butyl-3-(2,4-dimethoxyphenyl)ureidomethyl]phenoxy}-2-methylpropionate, mp 80-81°C;

72) Ethyl 2-{4-[3-(2,4-difluoro-6-methoxyphenyl)-1-(1,1-dimethyloctyl)ureidomethyl]phenoxy}-2-methylpropionate, mp 57-59°C;

73) Ethyl 2-{4-[3-(2,4-dimethoxyphenyl)-1-(1,1-dimethoxyhexyl)ureidomethyl]phenoxy}-2-methylpropionate, pale tan oil;

74) Ethyl 2-{4-[3-chloro-2-thienyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, yellow-tan oil;

75) 3-(2,4-Dimethoxyphenyl)-l-heptyl-1-{2-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]ethyl}urea, tan oil;

76) 2-(4-{2-[1-Heptyl-3-(2,4,6-trimethoxyphenyl)ureido]ethyl}phenoxy)-2-methylpropionic acid, mp 100-102°C;

77) 2-(4-{2-[1-Heptyl-3-(2,4,6-trimethylphenyl)ureido]ethyl}phenoxy)-2-methylpropionic acid, mp 53-103°C (glass);

78) 2-(4-{2-[1-Heptyl-3-(2,4,6-trichlorophenyl)ureido]ethyl}phenoxy)-2-methylpropionic acid, mp 47-55°C;

79) 2-(4-{2-[3-(2,6-Diisopropylphenyl)-1-heptylureido]ethyl}phenoxy)-2-methylpropionic acid, mp 56-57°C;

80) 1-{2-[4-(2-Hydroxy-1,1-dimethylethoxy)phenyl]ethyl}-3-(2,4-dimethoxyphenyl)-1-(6,6-dimethylheptyl)urea, colourless oil;

81) 2-(4-{2-[3-(2,4-Dimethoxyphenyl)-1-(3,3-dimethylbutyl)ureido]eth yl} phenoxy)-2-methylpropionic acid, 145-147°C;

82) 5-(4-{2-[3-(2,6-Dimethoxyphenyl)-1-heptylureido]ethyl}phenoxy)-2,2-dimethylvaleric acid, tan oil;

83) 2-(4-{3-[3-(2,6-Dimethoxyphenyl)-1-heptylureido]propyl}phenoxy)-2-methylpropionic acid, yellow oil;

84) Ethyl 2-(4-(1-heptyl-3-(2-tolyl)ureidomethyl]phenoxy}-2-methylpropanoate, colourless oil;

85) Ethyl 2-{4-[N'-(2,6-dimethylphenyl)-N-heptylureidomethyl]phenoxy}-2-methylpropionate, mp 68-70°C;

86) Ethyl 2-{4-[N'-(4-bromo-2,6-dimethylphenyl)-N-heptylureidomethyl]phenoxy}-2-methylpropionate, mp 72-74°C;

87) Ethyl 2-{4-[1-heptyl-3-(2-isopropylphenyl)ureidomethyl]phenoxy}-2-methylpropionate, mp 38-39°C;

88) Ethyl 2-{4-[1-heptyl-3-(2-isopropyl-6-methylphenyl)ureidomethyl]-phenoxy}-2-methylpropionate, mp 88-90°C;

89) Ethyl 2-{4-[3-(2,6-diisopropylphenyl-1-heptylureidomethyl]phenoxy}-2-methylpropionate, mp 135-136°C;

90) Ethyl 2-{4-[1-heptyl-3-(1-methoxy-2-naphthyl)ureidomethyl]phenoxy}-2-methylpropionate, pale green oil;

91) Ethyl 2-(4-{1-[2-fluoro-6-(4-pivaloylbenzyloxy)]-3-heptylureidomethyl}phenoxy)-2-methylpropionate, colourless oil;

92) Ethyl 2-(4-{3-[2-(4-t-butylbenzyloxy)-4-methoxyphenyl]-1-heptylureidomethyl}phenoxy)-2-methylpropionate, pale tan oil;

93) Ethyl 2-[4-(3-{2-fluoro-6-[4-(1-hydroxy-2,2-dimethylpropyl)benzyloxy]phenyl}-1-heptylureidomethyl)phenoxy]-2-methylpropionate, almost colourless oil;

94) Ethyl 2-(4-{3-[2,4-dichloro-6-(4-pivaloylbenzyloxy)phenyl]-1-heptylureidomethyl}phenoxy)-2-methylpropionate, pale yellow gum;

95) 3-(2,4-Dimethoxyphenyl)-1-heptyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)benzyl]urea, yellow oil;

96) 2-{4-[3-(2,6-Difluorophenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionic acid, no mp (amorphous solid);

97) Ethyl 2-{4-[3-(2-cyclohexylmethoxy-6-methoxyphenyl)-1-heptylureidomethyl]phenoxy}-2-methylpropionate, pale tan oil; and

98) 2-(4-{2-[3-(2,6-Dimethoxyphenyl)ureido]ethyl}phenoxy)-2-methylpropionic acid, mp 159-160°C.

Pharmaceutical Formulation Examples

[0038] In the following Examples, the "active ingredient" is any compound of formula (I) as hereinbefore defined, preferably one of the compounds of Synthetic Examples 1 to 98.

Tablet
	Per tablet
Active Ingredient	5.0 mg
Lactose	82.0 mg
Starch	10.0 mg
Povidone	2.0 mg
Magnesium Stearate	1.0 mg

[0039] Mix together the active ingredient, lactose and starch. Granulate the powders using a solution of povidone in purified water. Dry the granules, add the magnesium stearate and compress to produce 100mg tablets.

Controlled release tablet	Per tablet
Active ingredient	500 mg
Hydroxypropylmethylcellulose (Methocel K4M Premium)	112 mg
Lactose B.P.	53 mg
Povidone B.P.C.	28 mg
Magnesium Stearate	7 mg
	mg

[0040] The formulation may be prepared by wet granulation of the first three ingredients with the solution of povidone, followed by addition of the magnesium stearate and compression.

Capsule
	Per capsule
Active ingredient	250 mg
Lactose B.P.	143 mg
Sodium Starch Glycollate	25 mg
Magnesium Stearate	2 mg
	mg

[0041] Capsules may be prepared by admixing the ingredients of the formulation and filling two-part hard gelatin capsules with the resulting mixture.

Controlled release capsule
	Per capsule
Active ingredient	250 mg
Microcrystalline Cellulose	125 mg
Lactose B.P.	125 mg
Ethyl Cellulose	13 mg
	mg

[0042] The controlled-release capsule formulation may be prepared by extruding a mixture of the first three ingredients, then spheronising and drying the extrudate. The dried pellets are coated with the ethyl cellulose as a controlled-release membrane and filled into two-part hard gelatin capsules.

Powder capsule for inhalation
	Per capsule
Active Ingredient (0.5-7.0µm powder)	4.0 mg
Lactose (30-90µm powder)	46.0 mg
	mg

[0043] The powders were mixed until homogeneous and filled into suitably sized hard gelatin capsules (50mg per capsule).

Injectable solution
Active ingredient	101 mg
Glycerol formal	3.5 ml

[0044] The active ingredient was dissolved in the glycerol formal by shaking the mixture for 2-3 minutes. The resulting solution was distributed into ampoules under aseptic conditions.

Oral solution A
Active ingredient	414 mg
Glycerol formal	7.0 ml

[0045] The active ingredient was dissolved in the glycerol formal by shaking the mixture for 2-3 minutes. The resulting solution was distributed into ampoules under aseptic conditions.

Oral solution B
Active ingredient	179 mg
Labrafil M1944 CS (Gattefosse)	7.0 ml

[0046] The active ingredient was dissolved in the Labrafil M1944 CS by stirring the mixture at 40-45°C for 5-10 minutes. The resulting solution was distributed into ampoules under aseptic conditions.

Intramuscular injection formulation
Active ingredient	0.20 g
Benzyl Alcohol	0.10 g
Glycofurol 75	1.45 g
Water for Injection    q.s. to	3.00 ml

[0047] The active ingredient is dissolved in the glycofurol. The benzyl alcohol is added and dissolved, then water added to 3ml. The solution is filtered through a sterile micropore filter and sealed in sterile 3ml glass vials.

Inhalation aerosol
Active Ingredient (0.5-7.0µm powder)	200 mg
Sorbitan Trioleate	100 mg
Saccharin Sodium (0.5-7.0µm powder)	5 mg
Methanol	2 mg
Trichlorofluoromethane	4.2 g
Dichlorodifluoromethane    to	10.0 ml

[0048] The sorbitan trioleate and menthol are dissolved in the trichlorofluoromethane. The saccharin sodium and active ingredient are dispersed in the mixture which is then transferred to a suitable aerosol canister and the dichlorofluoromethane injected through the valve system. This composition provides 2mg of active ingredient in each 100µl dose.

Syrup formulation
Active ingredient	0.25 g
Sorbitol Solution	1.50 g
Glycerol	1.00 g
Sodium Benzoate	0.0050 g
Flavour	0.0125 ml
Purified Water    q.s. to	5.0 ml

[0049] The sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and then made up to the required volume with the purified water.

Suppository formulation
	Per suppository
Active ingredient (63µm)*	250 mg
Hard Fat, BP (Witepsol H15 - Dynamit Nobel)	1770 mg
	mg

* The active ingredient is used as a powder wherein at least 90% of the particles are of 63µm diameter or less.

[0050] One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at a maximum temperature of 45°C. The active ingredient is sifted through a 200µm sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension which is stirred until homogenous. The entire suspension is then passed through a 250µm stainless steel screen and allowed to cool to 40°C with continuous stirring. At a temperature of 38-40°C, 2.0g aliquots of the mixture are filled into suitable plastic moulds and the suppositories allowed to cool to room temperature.

Pessary formulation
	Per pessary
Active ingredient (63µm)	250 mg
Anhydrous Dextrose	380 mg
Potato Starch	363 mg
Magnesium Stearate	7 mg
	mg

[0051] The ingredients are mixed directly and pessaries prepared by compression of the resulting mixture.

Biological Assays

[0052] 

(i) In vitro assay for the inhibition of ACAT activity
ACAT activity was determined as described by Ross et al by the incorporation of [¹⁴C]oleoyl-CoA into cholesterol [¹⁴C]oleate using hepatic microsomes as the source of both ACAT and cholesterol. Microsomes were prepared from the livers of male CD rats fed a 0.4% cholesterol/0.2% cholic acid diet 3.5 days before sacrifice. Various concentrations of a test compound were preincubated with a 0.5mg/ml microsomal suspension and after 15 minutes a 50µg aliquot was removed and incubated with 25µM of [¹⁴C]-enriched oleoyl-CoA for 4 minutes. The reaction was terminated by the addition of lml of ethanol and 4ml of hexane. After shaking, the hexane layer was removed and evaporated to dryness. The hexane extract was then reconstituted in 150µl of HPLC solvent and injected on to a B&J OD5 Reverse Phase C18 column using an isocratic mobile phase of acetonitrile: isopropanol:heptane (50:40:10) in 0.5% acetic acid at a flow rate of 1.0ml/min. The product of the reaction, [¹⁴C]oleoyl cholesterol, was measured using a Flow One radiometric detector. The ACAT IC₅₀ value for each compound was determined from a plot of % inhibition from control vs inhibitor concentration.
The IC₅₀s for the compounds of Synthetic Examples 1 to 3 were 4.5µM, 3.4µM and 7.6µM respectively.

(ii) Determination of hypolipidemic activity in cholesterol-cholic acid fed rats
Male Sprague-Dawley rats (CD, Charles River) each weighing 200-300g were used. Hypercholesterolemia was induced in the rats by administration of a diet enriched to 0.4% cholesterol, 0.2% cholic acid. Prior to the administration of the diet, blood samples were collected under halothane anesthesia by cardiac puncture to determine baseline lipid levels. The blood was allowed to clot and serum was obtained for the analysis of total cholesterol, dextran-precipitable lipoproteins cholesterol (VLDL + LDL) and total triglycerides. The rats were divided into groups so that each group had similar average baseline serum lipid levels. Five days after the initial blood sampling, administration of each test compound and the cholesterol-cholic acid-enriched diet was begun. Compounds to be tested by gavage were administered b.i.d. in either 0.5% methyl cellulose or 5% sodium bicarbonate at 9:00 a.m. and 3:00 p.m. for three days and at 9:00 a.m. on the fourth day. Compounds administered as part of the diet were dissolved in ethanol and sprayed on to the diet. The ethanol was allowed to evaporate and the diet given to the rats for three days. On the fourth day, blood samples were collected and the final serum lipid levels determined. All blood samplings were taken after a four-hour fast.
The compound of Synthetic Example 1 at a dose of 25mg/kg reduced LDL-cholesterol by 55% and at a dose of 50mg/kg by 67%. The corresponding figures for the compound of Synthetic Example 2 were 5mg/kg (41-71%) and 25mg/kg (61%) and for the compound of Synthetic Example 3 were 0.5mg/kg (90%) and 2mg/kg (74%).

Claims

1. A compound of formula (I)

wherein

Ar is   a mono- or bicyclic aromatic group optionally containing one or two heteroatoms independently selected from nitrogen, oxygen and sulphur, said group being optionally substituted by one or more atoms or groups independently selected from halogen, nitro, amino, -NRR¹ where R and R¹ are independently selected from hydrogen, C_1-8 alkyl and C_1-8 alkanoyl, cyano, carboxyalkoxy, alkoxycarbonylalkoxy, C_1-8 alkyl (including cycloalkyl and cycloalkylalkyl), C_1-8 alkoxy (including cycloalkoxy and cycloalkylalkoxy), C_1-8 thioalkyl, said alkyl, alkoxy and/or thioalkyl group(s) being optionally substituted by one or more halogen atoms, aryl, aryloxy, aralkyl and aralkyloxy, said aryl, aryloxy, aralkyl and/or aralkyloxy group(s) being optionally substituted by one or more atoms or groups independently selected from halogen, alkyl, alkoxy, alkanoyl, hydroxyalkyl, perfluoroalkyl, perfluoroalkoxy, carboxyalkoxy, alkoxycarbonylalkoxy, and C_3-8 polyether groups containing from one to three oxygen atoms;

D is   -CH₂-, -NH-, or -O-;

E is   -N〈 or -CH〈;

G is   hydrogen, C_1-12 straight, branched, or cyclic alkyl, or aralkyl, said aralkyl group being optionally substituted by one or more atoms or groups independently selected from halogen, amino, N-(C_1-6 alkyl)amino, N,N-di(C_1-6 alkyl)amino, C_1-6 alkyl and C_1-6 alkoxy, or a C_3-8 polyether group containing one to three oxygen atoms;

J is   a bond or C_1-6 straight or branched alkylene;

n is   an integer of from 0 to 10;

R and R¹   are as hereinbefore defined; and

K is   -CH₂OH, -CHO, -CONHCH₂CONH₂, -CONH(C_1-6 alkyl), -OC(C_1-4 alkyl)₂OCOheteroaryl, -CO₂R² where R² is hydrogen, C_1-8 alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or a C_3-8 polyether group containing from one to three oxygen atoms, or -CONHAr' where Ar' is phenyl optionally substituted by one or more atoms or groups selected from fluorine, nitro, -NRR¹ where R and R¹ are as hereinbefore defined, C_1-6 alkyl and C_1-6 alkoxy, said alkyl and/or alkoxy group(s) being optionally substituted at the terminal carbon by -CO₂R³ where R³ is C_1-6 alkyl;

and salts and physiologically functional derivatives thereof.

2. A compound of formula (I) as shown in Claim 1, wherein

Ar is   phenyl or naphthyl substituted by one or more atoms or groups independently selected from halogen, C_1-8 alkyl C_1-8 alkoxy (including cycloalkylalkoxy), said alkyl and/or alkoxy group(s) being optionally substituted by one or more halogen atoms, C_1-8 thioalkyl, aryl, aryloxy and aralkyloxy, said aralkyloxy group being optionally substituted by alkyl, alkanoyl or hydroxyalkyl;

D is   -NH- or -O-;

E is   -X〈;

G is   C_5-8 straight or branched alkyl, (4-halophenyl)C_1-3 alkyl, or [4-di(C_1-6 alkyl)aminophenyl]C_1-3 alkyl;

J is   C_1-3 alkylene;

n is   an integer of from 0 to 4;

R and R¹   are respectively hydrogen and C_1-4 alkyl or are both C_1-4 alkyl; and

K is   -CO₂R² where R² is hydrogen or C_1-4 alkyl, or -CH₂OH;

and salts and physiologically functional derivatives thereof.

3. A compound of formula (I) as claimed in Claim 1, which compound is selected from

2-(4-{2-[3-(2,4-dimethoxyphenyl)-1-heptylureido]ethyl}phenoxy)-2-methylpropionic acid,

2-(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}phenoxy)-2-methylpropionic acid;

2-(4-[3-(2,4-dimethoxyphenyl)-1-heptylureidomethyl]phenoxy)-2-methylpropionic acid,

2-{4-[1-heptyl-3-(2,4,6-trichlorophenyl)ureidomethyl]phenoxy}-2-methylpropionic acid,

2-{4-[1-(3,3-dimethylbutyl)-3-(2,4-dimethoxyphenyl)ureidomethyl]-phenoxy}-2-methylpropionic acid,

3-(2,4-dimethoxyphenyl)-1-heptyl-1-[4-(2-hydroxy-1-methylethoxy) benzyl]urea,

3-(2,4-dimethylphenyl)-1-heptyl-1-[4-(5-hydroxy-4,4-dimethylpentyloxy)benzyl]urea

and their physiologically acceptable salts and physiologically functional derivatives.

4. A compound of formula (I) as claimed in any of Claims 1 to 3, or a physiologically functional derivative thereof, for use as a therapeutic agent.

5. A compound of formula (I) as claimed in any of Claims 1 to 3, or a physiologically functional derivative thereof, for use in the prophylaxis or treatment of a clinical condition for which an ACAT inhibitor and/or a fibrate is indicated.

6. A compound of formula (I) as claimed in any of Claims 1 to 3, or a physiologically functional derivative thereof, for use in the prophylaxis or treatment of atherosclerosis.

7. Use of a compound of formula (I) as claimed in any of Claims 1 to 3, or of a physiologically functional derivative thereof, in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which an ACAT inhibitor and/or a fibrate is indicated.

8. Use of a compound of formula (I) as claimed in any of Claims 1 to 3, or of a physiologically functional derivative thereof, in the manufacture of a medicament for the prophylaxis or treatment of atherosclerosis.

9. A medicament comprising a compound of formula (I) as claimed in any of Claims 1 to 3, or a physiologically functional derivative thereof, a pharmaceutically acceptable carrier and, optionally, one or more other physiologically active agents for use in the prophylaxis or treatment of a clinical condition for which an ACAT inhibitor and/or a fibrate is indicated.

10. A medicament as claimed in Claim 9 for use in the prophylaxis or treatment of atherosclerosis.

11. A medicament as claimed in Claim 9 or 10 which is in the form of a tablet or capsule.

12. A process for the preparation of a compound of formula (I) wherein D is -NH- and E is -N〈 as claimed in Claim 1 which comprises reacting a compound of formula (II)

wherein n, G, J, R and R¹ are as defined in Claim 1 and K' is as defined for K in Claim 1 or is a suitably protected form thereof, with a compound of formula (III)

        Ar-NCO     (III)

wherein Ar is as defined in Claim 1, typically in an aprotic polar solvent, for example dichloromethane and, if necessary, deprotecting the product.

13. A method for the preparation of a medicament as claimed in Claim 9 or 10 which comprises

(a) preparing a compound of formula (I) or a physiologically functional derivative thereof by a process as claimed in Claim 12 and

(b) admixing the product from step (a) with a pharmaceutically acceptable carrier and, optionally, one or more other physiologically active agents.

14. A method as claimed in Claim 13 which comprises an additional step (c) wherein the admixture from step (b) is formed into a tablet or capsule.

Ansprüche

1. Eine Verbindung der Formel (I)

worin

Ar   eine mono- oder bicyclische aromatische Gruppe ist, die gegebenenfalls ein oder zwei Heteroatome enthält, die unabhängig ausgewählt sind aus Stickstoff, Sauerstoff und Schwefel, wobei die Gruppe gegebenenfalls mit einem oder mehreren Atomen oder Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, Nitro, Amino, -NRR¹, worin R und R¹ unabhängig ausgewählt sind aus Wasserstoff, C_1-8 Alkyl und C_1-8 Alkanoyl, Cyano, Carboxyalkoxy, Alkoxycarbonylalkoxy, C_{1- 8}-Alkyl (einschließlich Cycloalkyl und Cycloalkylalkyl), C_1-8-Alkoxy (einschließlich Cycloalkoxy und Cycloalkylalkoxy), C_1-8-Thioalkyl, wobei die Alkyl-, Alkoxy- und/oder Thioalkylgruppe(n) gegebenenfalls mit einem oder mehreren Halogenatomen substituiert ist (sind), Aryl, Aryloxy, Aralkyl und Aralkyloxy, wobei die Aryl-, Aryloxy-, Aralkyl- und/oder Aralkyloxygruppe(n) gegebenenfalls mit einem oder mehreren Atomen oder Gruppen substituiert ist (sind), die unabhängig ausgewählt sind aus Halogen, Alkyl, Alkoxy, Alkanoyl, Hydroxyalkyl, Perfluoralkyl, Perfluoralkoxy, Carboxyalkoxy, Alkoxycarbonylalkoxy und aus C_3-8-Polyethergruppen, die ein bis drei Sauerstoffatome enthalten;

D   -CH₂-, -NH- oder -O- ist;

E   -N< oder -CH< ist;

G   Wasserstoff, eine geradkettige, verzweigte oder cyclische C_1-12-Alkyl- oder Aralkylgruppe ist, wobei die Aralkylgruppe gegebenenfalls mit einem oder mehreren Atomen oder Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, Amino, N-(C_1-6-Alkyl)-amino, N,N-Di(C_1-6-alkyl)-amino, C_1-6-AlkYl und C_1-6-Alkoxy, oder eine C_3-8-Polyethergruppe, die ein oder mehrere Sauerstoffatome enthält;

J   eine Bindung oder für ein geradkettiges oder verzweigtes C_1-6-Alkylen ist;

n   eine Zahl von 0 bis 10 ist;

R und R¹   wie hier zuvor definiert sind; und

K   -CH₂OH, -CHO, -CONHCH₂CONH₂, -CONH(C_1-6-Alkyl), -OC(C_1-4-Alkyl)₂OCO-heteroaryl, -CO₂R², worin R² für Wasserstoff, C_1-8-Alkyl, Aryl, Heteroaryl, Aralkyl, Heteroaralkyl steht, oder eine C_3-8-Polyethergruppe, die ein bis drei Sauerstoffatome enthält, oder -CON-HAr , worin Ar für Phenyl steht, das gegebenenfalls mit einem oder mehreren Atomen oder Gruppen substituiert ist, die ausgewählt sind aus Fluor, Nitro,-NRR¹, worin R und R¹ wie hier zuvor definiert sind, C_1-6-Alkyl und C_1-6-Alkoxy, wobei die Alkyl- und/oder Alkoxygruppe(n) gegebenenfalls am endständigen Kohlenstoff mit -CO₂R³ substituiert sind, worin R³ für C_1-6-Alkyl steht;

und die Salze und physiologisch funktionellen Derivate davon.

2. Eine Verbindung der Formel (I) nach Anspruch 1, worin

Ar   Phenyl oder Naphthyl ist, das mit einem oder mehreren Atomen oder Gruppen substituiert ist, die unabhängig ausgewählt sind aus Halogen, C_1-8-Alkyl, C_1-8-Alkoxy (einschließlich Cycloalkylalkoxy), wobei die Alkyl- und/oder Alkoxygruppe(n) gegebenenfalls mit einem oder mehreren Halogenatomen substituiert ist (sind), C_1-8-Thioalkyl, Aryl, Aryloxy und Aralkyloxy, wobei die Aralkyloxygruppe gegebenenfalls mit Alkyl substituiert ist, Alkanoyl oder Hydroxyalkyl;

D   -NH- oder -O- ist;

E   -N< ist,

G   geradkettiges oder verzweigtes C_5-8-Alkyl, (4-Halogenphenyl)-C_1-3-alkyl oder [4-Di(C_1-6-alkyl)-aminophenyl]-C_1-3-alkyl ist;

J   C_1-3-Alkylen ist;

n   eine Zahl von 0 bis 4 ist;

R und R¹   Wasserstoff bzw. C_1-4-Alkyl oder beide C_1-4-Alkyl sind; und

K   -CO₂R² ist, worin R² für Wasserstoff oder C_1-4-Alkyl oder -CH₂OH steht;

und die Salze und physiologisch funktionellen Derivate davon.

3. Eine Verbindung der Formel (I) nach Anspruch 1, wobei die Verbindung ausgewählt ist aus

2-(4-{2-[3-(2,4-Dimethoxyphenyl)-1-heptylureido]-ethyl}-phenoxy)-2-methylpropionsäure,

2-(4-{2-[3-(2,4-Difluorphenyl)-1-heptylureido]-ethyl}-phenoxy)-2-methylpropionsäure,

2-(4-[3-(2,4-Dimethoxyphenyl)-1-heptylureidomethyl]-phenoxy)-2-methylpropionsäure,

2-{4-[1-Heptyl-3-(2,4,6-trichlorphenyl)-ureidomethyl]-phenoxy}-2-methylpropionsäure,

2-{4-[1-(3,3-Dimethylbutyl)-3-(2,4-dimethoxyphenyl)-ureidomethyl]-phenoxy}-2-methylpropionsäure,

3-(2,4-Dimethoxyphenyl)-1-heptyl-1-[4-(2-hydroxy-1-methylethoxy)-benzyl]-harnstoff,

3-(2,4-Dimethylphenyl)1-heptyl-1-[4-(5-hydroxy-4,4-dimethylpentyloxy)-benzyl]-harnstoff,

und ihre physiologisch verträglichen Salze und physiologisch funktionellen Derivate.

4. Eine Verbindung der Formel (I) nach irgendeinem der Ansprüche 1 bis 3 oder ein physiologisch funktionelles Derivat davon zur Verwendung als therapeutisches Mittel.

5. Eine Verbindung der Formel (I) nach irgendeinem der Ansprüche 1 bis 3 oder ein physiologisch funktionelles Derivat davon zur Verwendung bei der Prophylaxe oder Behandlung eines klinischen Zustandes, für den ein ACAT-Inhibitor und/oder ein Fibrat indiziert ist.

6. Eine Verbindung der Formel (T) nach irgendeinem der Ansprüche 1 bis 3 oder ein physiologisch funktionelles Derivat davon zur Verwendung bei der Prophylaxe oder Behandlung Arteriosklerose.

7. Verwendung einer Verbindung der Formel (I) nach irgendeinem der Ansprüche 1 bis 3 oder ein physiologisch funktionelles Derivat davon zur Herstellung eines Medikamentes zur Prophylaxe oder Behandlung eines klinischen Zustandes, für den ein ACAT-Inhibitor oder ein Fibrat indiziert ist.

8. Verwendung einer Verbindung der Formel (I) nach irgendeinem der Ansprüche 1 bis 3 oder ein physiologisch funktionelles Derivat davon zur Herstellung eines Medikaments zur Prophylaxe oder Behandlung von Arteriosklerose.

9. Ein Medikament, das umfaßt eine Verbindung der Formel (I) nach irgendeinem der Ansprüche 1 bis 3 oder ein physiologisch funktionelles Derivat davon, einen pharmazeutisch verträglichen Träger und gegebenenfalls ein oder mehrere physiologisch Wirkstoffe zur Verwendung bei der Prophylaxe oder Behandlung eines klinischen Zustandes, für den ein ACAT-Inhibitor und/oder ein Fibrat indiziert ist.

10. Ein Medikament nach Anspruch 9 zur Verwendung bei der Prophylaxe oder Behandlung von Arteriosklerose.

11. Ein Medikament nach Anspruch 9 oder 10, das in Form einer Tablette oder Kapsel vorliegt.

12. Ein Verfahren zur Herstellung einer Verbindung der Formel (I), worin D für -NH- steht und E für -N< steht, nach Anspruch 1, das umfaßt die Umsetzung einer Verbindung der Formel (II)

worin n, G, J, R und R¹ wie in Anspruch 1 definiert sind und K wie für K in Anspruch 1 definiert ist oder eine geeignet geschützte Form davon ist, mit einer Verbindung der Formel (III)

        Ar-NCO     (III),

worin Ar die in Anspruch 1 gegebene Definition besitzt, typischerweise in einem aprotischen polaren Lösungsmittel, beispielsweise Dichlormethan, und, falls notwendig, die Schutzgruppenentfernung von dem Produkt.

13. Ein Verfahren zur Herstellung eines Medikamentes nach Anspruch 3 oder 10, das umfaßt

(a) Herstellen einer Verbindung der Formel (I) oder eines physiologisch funktionellen Derivates davon durch ein Verfahren nach Anspruch 12; und

(b) Mischen des Produkts aus Schritt (a) mit einem pharmazeutisch verträglichen Träger und gegebenenfalls einem oder mehreren weiteren physiologischen Wirkstoffen.

14. Verfahren nach Anspruch 13, das einen zusätzlichen Schritt (c) umfaßt, in dem das Gemisch aus Schritt b zu einer Tablette oder Kapsel geformt wird.

Revendications

1. Composé de formule (I)

   dans laquelle

Ar est un groupe aromatique mono- ou bicyclique, contenant éventuellement un ou deux hétéroatomes choisis d'une manière indépendante parmi l'azote, l'oxygène et le soufre, ledit groupe étant éventuellement substitué par un ou plusieurs atomes ou groupes choisis d'une manière indépendante parmi les halogènes, les groupes nitro, amino, -NRR¹, où R et R¹ sont choisis d'une manière indépendante parmi l'hydrogène, les groupes alkyle en C_1-8 et alcanoyle en C_1-8, cyano, carboxyalcoxy, alcoxycarbonylalcoxy, alkyle en C_1-8 (y compris cycloalkyie et cycloalkylalkyle), alcoxy en C_1-8 (y compris cycloalcoxy et cycloalkylalcoxy), thioalkyle en C_1-8, ledit ou lesdits groupes alkyle, alcoxy et/ou thioalkyle étant éventuellement substitués par un ou plusieurs atomes d'halogène, aryle, aryloxy, aralkyle et aralkyloxy, ledit ou lesdits groupes aryle, aryloxy, aralkyle et/ou aralkyloxy étant éventuellement substitués par un ou plusieurs atomes ou groupes choisis d'une manière indépendante parmi les halogènes et les groupes alkyle, alcoxy, alcanoyle, hydroxyalkyle, perfluoralkyle, perfluoralcoxy, carboxyalcoxy, alcoxycarbonylalcoxy, et les groupes polyéther en C_3-8 contenant un à trois atomes d'oxygène ;

D est - CH₂-, -NH- ou -O- ;

E est -N〈 ou -CH〈 ;

G est un hydrogène ou un groupe alkyle à chaîne droite ou ramifiée, ou cyclique en C_1-12, ou aralkyle, ledit groupe aralkyle étant éventuellement substitué par un ou plusieurs atomes ou groupes choisis d'une manière indépendante parmi les halogènes, les groupes amino, N-(alkyle en C_{1- 6})amine, N,N-di(alkyle en C_1-6)amine, alkyle en C_1-6 et alcoxy en C_1-6, ou encore un groupe polyéther en C_3-8 contenant un à trois atomes d'oxygène ;

J est une liaison ou un groupe alkylène en C_1-6 à chaîne droite ou ramifiée ;

n est un entier de 0 à 10 ;

R et R¹ sont tels que définis ci-dessus ; et

K est -CH₂OH, -CHO, -CONHCH₂CONH₂, -CONH(alkyle en C_1-6), -OC(alkyle en C_1-4)₂OCO-hétéroaryle, -CO₂R², où R² est un hydrogène ou un groupe alkyle en C_1-8, aryle, hétéroaryle, aralkyle, hétéroaralkyle, ou un groupe polyéther en C_3-8 contenant de 1 à 3 atomes d'oxygène, ou bien-CONHAr', où Ar' est un groupe phényle éventuellement substitué par un ou plusieurs atomes ou groupes choisis parmi le fluor, les groupes nitro, -NRR¹, où R et R¹ sont tels que définis ci-dessus, alkyle en C_1-6 et alcoxy en C_1-6, ledit ou lesdits groupes alkyle et/ou alcoxy étant éventuellement substitués au niveau du carbone terminal par -CO₂R³, où R³ est un groupe alkyle en C_1-6 ;

   et ses sels et dérivés à fonctionnalité physiologique.

2. Composé de formule (I) selon la revendication 1, dans laquelle

Ar est le groupe phényle ou naphtyle, substitué par un ou plusieurs atomes ou groupes choisis d'une manière indépendante parmi les halogènes et les groupes alkyle en C_1-8, alcoxy -en C_1-8 (y compris cycloalkylalcoxy), ledit ou lesdits groupes alkyle et/ou alcoxy étant éventuellement substitués par un ou plusieurs atomes d'halogène, thioalkyle en C_1-8, aryle, aryloxy et aralkyloxy, ledit groupe aralkyloxy étant éventuellement substitué par des substituants alkyle, alcanoyle ou hydroxyalkyle ;

D est -NH- ou -O- ;

E est -N〈 ;

G est un groupe alkyle à chaîne droite ou ramifiée en C_5-8, (4-halogénophényl)(alkyle en C_1-3) ou [4-di(alkyle en C_1-6)aminophényl](alkyle en C_1-3) ;

J est un groupe alkylène en C_1-3 ;

n est un entier de 0 à 4;

R et R¹ sont respectivement un hydrogène et un groupe alkyle en C_1-4, ou représentent tous les deux des groupes alkyle en C_1-4 ; et

K est -CO₂R² où R² est un hydrogène ou un groupe alkyle en C_1-4, ou-CH₂OH ;

   et ses sels et dérivés à fonctionnalité physiologique.

3. Composé de formule (I) selon la revendication 1, lequel composé est choisi parmi les composés suivants :

acide 2-(4-(2-[3-(2,4-diméthoxyphényl)-1-heptyl-uréidojéthyl)phénoxy)-2-méthylpropionique

acide 2-(4-(2-[3-(2,4-difluorophényl)-1-heptyl-uréido]éthyl)phénoxy)-2-méthylpropionique

acide 2-(4-[3-(2,4-diméthoxyphényl)-1-heptyl-uréidométhyl)phénoxy)-2-méthylpropionique

acide 2-(4-[1-heptyl-3-(2,4,6-trichlorophényl)uréido-méthyl]phénoxy)-2-méthylpropionique

acide 2-(4-[1-(3,3-diméthylbutyl)-3-(2,4-diméthoxyphényl)uréidométhyl]phénoxy)-2-méthylpropionique

3-(2,4-diméthoxyphényl)-1-heptyl-1-[4-(2-hydroxy-1-méthyléthoxy)benzyl]urée

3-(2,4-diméthylphényl)-1-heptyl-1-[4-(5-hydroxy-4,4-diméthylpentyloxy)benzyl]urée

   et leurs sels acceptables d'un point de vue physiologique et leurs dérivés à fonctionnalité physiologique.

4. Composé de formule (I) selon l'une quelconque des revendications 1 à 3, ou l'un de ses dérivés à fonctionnalité physiologique, pour utilisation en tant qu'agent thérapeutique.

5. Composé de formule (I) selon l'une quelconque des revendications 1 à 3, ou l'un de ses dérivés à fonctionnalité physiologique, pour utilisation dans la prophylaxie ou le traitement d'un état clinique pour lequel est indiqué un inhibiteur de l'ACAT et/ou un fibrate.

6. Composé de formule (I) selon l'une quelconque des revendications 1 à 3, ou l'un de ses dérivés à fonctionnalité physiologique, pour utilisation dans la prophylaxie ou le traitement de l'athérosclérose.

7. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 3, ou d'un de ses dérivés à fonctionnalité physiologique, pour préparer un médicament destiné à la prophylaxie ou au traitement d'un état clinique pour lequel est indiqué un inhibiteur de l'ACAT et/ou un fibrate.

8. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 3, ou d'un de ses dérivés à fonctionnalité physiologique, dans la préparation d'un médicament destiné à la prophylaxie ou au traitement de l'athérosclérose.

9. Médicament comprenant un composé de formule (I) selon l'une quelconque des revendications 1 à 3, ou un de ses dérivés à fonctionnalité physiologique, un excipient acceptable d'un point de vue pharmaceutique, et éventuellement un ou plusieurs autres principes physiologiquement actifs, pour utilisation dans la prophylaxie ou le traitement d'un état clinique pour lequel est indiqué un inhibiteur de l'ACAT et/ou un fibrate.

10. médicament selon la revendication 9, pour utilisation dans la prophylaxie ou le traitement de l'athérosclérose.

11. Médicament selon la revendication 9 ou 10, qui se présente sous la forme d'un comprimé ou d'une gélule.

12. Procédé pour préparer un composé de formule (I), où D est -NH- et E est -N〈 selon la revendication 1, qui consiste à faire réagir un composé de formule (II)

   dans laquelle n, G, J, R et R¹ sont tels que définis dans la revendication 1 et K' est tel que défini pour K dans la revendication 1 ou est une forme convenablement protégée de ce dernier, avec un composé de formule (III)

        Ar-NCO     (III)

   dans laquelle Ar est tel que défini dans la revendication 1, typiquement dans un solvant aprotique polaire, par exemple le dichlorométhane, et, si nécessaire, à déprotéger le produit.

13. Procédé pour préparer un médicament selon la revendication 3 ou 10, qui consiste :

(a) à préparer un composé de formule (I) ou l'un de ses dérivés à fonctionnalité physiologique, par un procédé selon la revendication 12 ; et

(b) à mélanger au produit de l'étape (a) un excipient acceptable d'un point de vue pharmaceutique, et éventuellement un ou plusieurs autres principes physiologiquement actifs.

14. Procédé selon la revendication 13, qui comprend une étape additionnelle (c) dans laquelle le mélange provenant de l'étape (b) est transformé en un comprimé ou une gélule.